TARGETING ANTIGEN-INDUCED ER STRESS RESPONSE IN B-CELL CHRONIC LYMPHOCYTIC LEUKEM

靶向 B 细胞慢性淋巴细胞白血病中抗原诱导的 ER 应激反应

• 批准号: 8990582
• 负责人: Chih-Chi Andrew Hu
• 金额: $ 22.68万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-17 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8990582
• 关键词: TARGETING; ANTIGEN; INDUCED; ER; STRESS

DESCRIPTION (provided by applicant): Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. According to the National Cancer Institute, approximately 16,060 patients will be diagnosed with CLL and approximately 4,580 patients will die of CLL in the US in 2012. At the Moffitt Cancer Center in Tampa, Florida, we see about 200 new CLL patients each year. Although CLL initially responds to chemotherapy, the relapsed CLL occurs at a high rate and acquires chemoresistance. Therefore, CLL is still incurable. We propose to identify the critical mechanisms that CLL cells rely on for their survival and target one such mechanism to block or decelerate aggressive progression of CLL. Robust B cell receptor (BCR) signal transduction was suggested to be responsible for the rapid proliferation of CLL cells, leading to aggressive progression of disease. Although protein antigen has been suggested to trigger the growth and proliferation of CLL cells, this concept that antigen can drive malignant progression of CLL has not been recapitulated in an animal model. Therefore, we have created a novel antigen-specific CLL mouse model, in which we use a desired antigen to activate the BCR and drive malignant progression of CLL. When a B cell is stimulated by its cognate antigen, activation of the endoplasmic reticulum (ER) stress response occurs to support B cell growth and proliferation. We hypothesize that engagement of the BCR by protein antigen can activate the ER stress response in CLL cells to promote malignant progression of CLL in vivo. We have shown that the inositol-requiring enzyme-1 (IRE-1)/X-box- binding protein-1 (XBP-1) pathway of the ER stress response is critical for the survival of CLL cells. Blocking the expression of XBP-1 by a novel small-molecule chemical inhibitor induces apoptosis in CLL cells in culture. To better understand the role of the IRE-1/XBP-1 pathway in the progression of CLL, we have genetically deleted the XBP-1 gene from our novel antigen-specific CLL mouse model. Using this innovative mouse model together with our novel small-molecule inhibitors, we will investigate the mechanisms by which blocking the IRE-1/XBP-1 pathway can decelerate antigen-induced aggressive progression of CLL in vivo. In cells with genetic deletion or chemical knockdown of XBP-1, we observed that IRE-1 is expressed at an elevated level and acquires a unique phosphorylation pattern. IRE-1 has been known for its roles in promoting cell survival and inducing apoptosis, but it is still unclear how IRE-1 accomplishes these two seemingly opposing tasks. We hypothesize that differential phosphorylation patterns may allow IRE-1 to associate with different interacting partners to carry out its functions in promoting survival or inducing apoptosis in CLL. Our goals in this proposal are summarized by two aims: 1) Target the IRE-1/XBP-1 pathway in antigen-induced aggressive progression of CLL in vivo; 2) Identify and investigate proteins that interact with IRE-1 to further understand how targeting the IRE-1/XBP-1 pathway can lead to stalled progression of CLL. Our goal is to establish the ER stress response as a useful target for the treatment of CLL.

描述（由申请人提供）：慢性淋巴细胞性白血病（CLL）是成人最常见的白血病。根据国家癌症研究所的数据，2012年将被诊断出约16,060名患者患有CLL，大约有4,580名患者将死于CLL。尽管CLL最初对化学疗法有反应，但复发的CLL以很高的速度发生并获得化学抗性。因此，CLL仍然无法治愈。我们建议确定CLL细胞依赖其生存的关键机制，并针对一种这种机制来阻止或减速CLL的攻击性进展。鲁棒的B细胞受体（BCR）信号转导指示CLL细胞的快速增殖，从而导致疾病的侵略性进展。尽管已建议蛋白质抗原触发CLL细胞的生长和增殖，但这种抗原可以驱动CLL恶性进展的概念尚未在动物模型中概括。因此，我们创建了一种新型的抗原特异性CLL小鼠模型，其中我们使用所需的抗原激活BCR并驱动CLL的恶性进展。当B细胞通过其同源抗原刺激B细胞时，会激活内质网应激反应以支持B细胞的生长和增殖。我们假设蛋白质抗原对BCR的参与可以激活CLL细胞中的ER应力反应，以促进体内CLL的恶性进展。我们已经表明，ER应激响应的肌醇提取酶-1（IRE-1）/X-box-结合蛋白-1（XBP-1）途径对于CLL细胞的存活至关重要。通过一种新型的小分子化学抑制剂阻断XBP-1的表达可诱导培养物中CLL细胞的凋亡。为了更好地了解IRE-1/XBP-1途径在CLL进展中的作用，我们从新型抗原特异性CLL小鼠模型中遗传删除了XBP-1基因。使用这种创新的小鼠模型以及我们的新型小分子抑制剂，我们将研究阻断IRE-1/XBP-1途径的机制，可以减速体内CLL的抗原诱导的侵袭性进展。在具有遗传缺失或XBP-1化学敲低的细胞中，我们观察到IRE-1在较高的水平上表达并获得独特的磷酸化模式。 IRE-1因其在促进细胞存活和诱导凋亡中的作用而闻名，但目前尚不清楚IRE-1如何完成这两个看似相反的任务。我们假设差异磷酸化模式可能使IRE-1与不同的相互作用伴侣相关联，可以在促进CLL中促进生存或诱导凋亡方面发挥其功能。我们在该提案中的目标总结了两个目的：1）靶向抗原引起的cll cll体内侵袭性进展中的IRE-1/XBP-1途径； 2）识别和研究与IRE-1相互作用的蛋白质，以进一步了解靶向IRE-1/XBP-1途径如何导致CLL的停滞进展。我们的目标是建立ER应力响应作为治疗CLL的有用目标。